We will explore the development of models of tolerance to and physical dependence on chloridiazepoxide and methaqualone by means of the subcutaneous implantation of pellets of these agents analogous to the models in use for morphine or those recently developed in our laboratory for barbiturates. We will utilize these models in a systematic assessment of the same sequence of regional cerebral metabolic events we have shown to occur at various stages in the transition from the acute depressant to the tolerant and dependent state with morphine and barbiturates. Since degrees of tolerance develop to the actions of drugs of abuse on the thermoregulatory and respiratory centers as well, the known cerebral metabolic effects of hypothermia and hypercapnia will also be considered. The adaptive metabolic events we have selected to assess include: (1) regional cerebral carbohydrate- aliphatic amino acid relationships in vivo and in vitro; (2) the spontaneous and stimulated release of gamma-aminobutyric acid from various brain regions in vitro; (3) the changes in threshold to depolarization in vitro; and (4) the effects of ranges of temperature and/or partial pressures of carbon dioxide on these metabolic relationships in vivo and in vitro. We expect these studies to provide information not presently available on the adaptation of functional regional cerebral metabolism to the effects of drugs of abuse on the central nervous system.